Overall Summary The goal of this Program Project is to develop approaches to reproduce the success of adoptive T cell transfer using chimeric antigen receptor (CAR) transduced T cells for hematologic malignancies to solid tumors, with a focus on thoracic malignancies (non-small cell lung cancer [NSCLC] and malignant pleural mesothelioma [MPM]. An important scientific theme in all of the projects is an exploration of the ability of CAR T cells to induce epitope spreading, that is, their ability to stimulate endogenous B and T cell responses against the tumor- a key component for success in solid tumors. This PO1 will have 3 projects which will be supported by 3 Cores. Project 1 will conduct clinical trials using CAR T cells. In Aim 1, we will continue a clinical trial in patients with NSCLC and MPM using a newly designed and improved anti-mesothelin-CAR construct. In Aim 2, we will conduct a Phase 1 clinical trial to evaluate the potential safety and clinical activity of a CAR targeted to tumor stroma (cancer associated fibroblasts) by engaging fibroblast activation protein (FAP). In future studies, we will design a third CAR T cell trial based on the results of these two trials and on new data from Projects 2 and 3. Project 2 will study ways to overcome heterogeneity in solid tumor CAR T cell therapy using preclinical studies that will integrate closely with our planned clinical trials. In Aim 1, we will conduct studies to evaluate the safety and efficacy of targeting tumor stroma using CARs targeted against anti-human fibroblast activation protein (FAP). In Aim 2, we will explore the key issue of mesothelin and FAP CARs being able to induce bystander effects and epitope spreading. In Aim 3, we will examine ways to augment this. Project 3 will conduct human biocorrelative studies. In Aim 1, we will study the persistence,trafficking, and function of CAR T cells in tumors. In Aim 2, we will evaluate the hypothesis that the CAR T cells used in our clinical trials can activate endogenous anti-tumor CD8 T cell responses (similar to the studies in Project 2). In Aim 3, we will characterize the polyclonality of T cell responses generated by epitope spreading after CAR T cell infusion in peripheral blood and tumors. We will benefit greatly from the unique environment of the newly established Penn Center for Cellular Immunotherapies (CCI) led by Dr. Carl June. These projects will be supported by an Administrative Core (with an internal and external advisory board), a Pathology/Sample Acquisition Core, and a Biostatistics/Bioinformatics/Data Management Core. Monthly Program Project meetings will be held. The PO1 has highly experienced leadership and the Project leaders and Core leaders have long track records of successful collaborations and publications. Each project is highly dependent on the other projects, requiring the Program Project format for success. The PO1 has high significance: achieving success rates with CAR T cells in solid tumors similar to that seen in leukemia would be a major paradigm shift in the treatment of solid tumors. 1